7-(2-(1-(phenylsulfonyl)-2-pyrrolidinylthio)acetamino)cephalosporanic acids

ABSTRACT

The invention relates to 7-(2-(1-(phenyl or substituted phenylsulfonyl)-2-pyrrolidinylthio)-acetamido)cephalosporanic acids as anti-bacterial agents and the intermediate (1-(phenyl- or substituted phenyl-sulfonyl)-2-pyrrolidinylthio)acetic acids employed in their production.

United States Patent 11 1 Wei et al.

[ 7-(2-[l-(PHENYLSULFONYLl-Z- PYRROLIDINYLTHIOlACETAMlNO)CEPH-ALOSPORANIC ACIDS [75] Inventors: Peter H. L. Wei, Springfield; CarlGochman, Philadelphia. both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

221 Filed: Mar. 18, 1974 1211 Appl. N0.: 452,011

[52] US. Cl 260/243 C; 260/239.6; 260/239.7;

260/326.42; 260/326.47; 424/246 [51] Int. Cl C07d 99/24 [58] Field ofSearch 260/243 C [56] References Cited UNITED STATES PATENTS 3.658.7994/1972 Eardley et al 260/243 C June 17, 1975 Primary ExaminerDonald G.Daus Assistant Examiner-Anne Marie T. Tighe Attorney, Agent, orFirm-Richard K. Jackson; Vito Victor Bellino 5 7 ABSTRACT 3 Claims, NoDrawings 7-(2-[1-(PHENYLSULFONYL)-2- in which YRR LID R is a memberselected from the group consisting of PORANIC ACIDS -H, alkyl of l to 3carbon atoms, halo, nitro, al- 5 kanoylamido of 2 to 6 carbon atoms andtrifluorometh l.

DESCRIPTION OF THE lNVhNTlON The inl ermediate carboxylic acids areprepared by In accordance with this invention there is provided areacting a thioglycolic acid with an appropriately subgroup of 7-(2-[l-(phenyland substituted phenylsulfostitutedN-(4,4-diethoxybutyl)benzene sulfonamide innyl)-2-pyrrolidinylthiolacetamido)cephalosporanic the presence of acatalytic amount of a mineral acid,

acids and salts of the formula 10 thusly 0C .,ll R

R so,

sem'oui L, :r\ .I :1 v a "J T g l v f\.

. r -scHc0 ch 5: l (l N H l CO H in which The intermediate carboxylicacid is coupled with the R is a member selected from the groupconsisting of 7-amino cephalosporanic acid derivative by either thealkyl 0f 1 t0 3 Carbon atoms, halo, Him), dehydrative coupling or mixedanhydride technique kanoylamido of 2 to 6 carbon atoms, andtrifluorocommonly employed in the production of amide linkmethyl; agesas in the field of polypeptide production. The free R is a memberselected from the group consisting of carboxyl group of the 7-aminocephalosporanic acid H and alkyl of l to 3 carbon atoms; derivative maybe converted to a salt (e.g. alkali metal, is 11 member Selected mm thegroup ccmsisting of ammonium or trialkylamine) before or after the coulkn yl xy 0f 2 t0 6 carbon atOmS, pling reaction by techniques well knownin the art.

x,\ l i t l t h'- CH f'h or when I v taken M1 th the q-wm'bom group.

M is a member selected from the group consisting of The preferredanti-bacterial agents of this invention an alk "16ml 11nd from thestandpoint of production economies are those In addition, this inventionprovides intermediate of the formula: compounds for the production ofthe cephalosporin derivatives described in the foregoing paragraph. Theintermediate [l-(ph'enyl and substituted phenyl- R 2sulfonyl)Lpyrrolidinylthiolacctic acids present the structural formulascacdiiii 8 t l r R (C 2 s l I y I 002'."

in wh ch R is a member selected from the group consisting of Cl, Br andNO- R is a member selected from the group consisting of -H and acetoxy;and M is a member selected from the group consisting of H, sodium andpotassium.

The cephalosporin derivatives of this invention have been found to beactive anti-bacterial agents effective against gram-positive andgram-negative test organisms as well as penicillin resistantstaphlococcus, in the well known and scientifically accepted agar serialdilution testing procedure. Thus. the cephalosporin derivatives of thisinvention are useful in the fields of comparative pharmacology and inmicrobiology and for the treatment of bacterial infections amenable totreatment with penicillin and cephalosporin derivatives. Theintermediate carboxylic acids of this invention are useful for thepreparation of the disclosed anti-bacterial ceph- 2O alosporinderivatives.

The following examples illustrate the preparation of representativeintermediate carboxylic acids and representative cephalosporanic acidderivatives of those carboxylie acid reactants. The cephalosporanic acidalkali metal salts were recovered in each instance, the free carboxylicacids being readily produced by known methods. The small amount ofresidual solvent present in some of the products exemplified is readilyremoved, if desired by vacuum stripping. The activity of each of thecephalosporin derivatives is provided for the specific bacterial strainsagainst which the compound exemplified was active at or below 250micrograms per milliliter. The representative nature of the bacterialstrains employed to demonstrate anti-bacterial activity are indicativeof the broader applicability of the compounds of this invention in thecontrol of bacterial infestations other than those specifically referredto in each of the following examples:

NE CA Nt'isxcria calurrlialix BA SU Bacillus .rubtilis BO BR Bordelellubmm'hisuplicu ES C O Escherichia 0011' SA PA Salmonella paralyplii KL PNKlelzriella pneunmniae ST AU Sluphyloc'm'cux aureus EXAMPLE l l-(p-Bromophenylsulfonyl)-2-pyrrolidinylthio]acetic Acidp-Bromo-N-(4,4-diethoxybutyl)benzene sulfonamide (3.8 grams, 0.01milliliter) and thioglycolic acid (1.0 gram) were dissolved indimethoxyethane and the solution was heated on a steam bath, in thepresence of a few drops of 6N HCl solution for 3 hours. After removal ofthe solvent, the residue was dissolved in henzene. The benzene solutionwas extracted with a dilute NaHCO- solution and extracted several timeswith benzene. The benzene extracts were dried over anhydrous MgSO Afterthe benzene was removed, the residue was recrystallized from a mixtureof diethyl ether and pentane to afford the title compound, m.p. 8689C.

Elemental Analysis for H,,BrNo.s.

Calc'd: C. 37.89; H, 3.7]; N, 3118. Found: C, 38.05; H. 3. 2; N. 3.74.

EXAMPLE ll l-(p-Acetamidophenylsulfonyl)-2-pyrrolidinylthio]acetic Acid.

5 The title compound (m.p. l47l49C. from CH CN) was prepared by asimilar procedure to that described in Example I except thatp-acetamido-N- (4,4-diethoxybutyl)benzene sulfonamide was utilized atroom temperature.

Elemental Analysis for C H,,.N ();,S

(alcdz C, 46.9]; H. 5.061N. 7.8 Found: C, 46.94; H. 5.09; 8 3

EXAMPLE 1]] l-(p-Nitrophenylsulfonyl)2-pyrrolidinylthio]acetic Acid.

The title compound (m.p. l-l38C. from benzene) was prepared by a similarprocedure to that described in Example I except that p-nitro-N-(4,4-diethoxybutyl)benzenc sulfonamide was utilized at room temperature.

Elemental Analysis for C H N O S lIIZC H Calcd: C. 42.54: H. 3.l4: N,7.94.

30 Found: C. 42.94; H, 4.26; N, 8.05.

EXAMPLE lV 7-(2-[1-(p-Bromophenylsulfonyl)-2-pyrroidinylthio]acetamido)cephalosporanic Acid.

To l-(p-bromophenylsulfonyl )-2-pyrrolidinylthio]acetic acid (0.76 gram,2 millimole) in 4 milliliter dimethylformamide was added carbonyldiimidazole (0.32 gram, 2 millimole) in one portion. The mixture wasstirred under nitrogen atmosphere for /2 hour and under vacuum for /2hour. To the above solution in an ice bath was added a cold solution of7-aminocephalos- 5 poranic acid (0.56 gram, 2 millimole) andtriethylamine (020 gram) in methlene chloride. The solution was stirredin an ice bath for 1 hour and at room temperature for l hour. Someinsoluble material was filtered off. The filtrate was evaporated underreduced pressure at approximately 30C. To the residue dissolved inmethylene chloride was added one milliliter of a 2M potassium Z-ethylhexanoate. Addition of anhydrous diethyl ether caused precipitation of asalt, which was collected, washed with diethyl ether and dried.

Elemental Analysis for C H .BrN .,o.s ,K:

7-(2-l l-(p-Nitrophenylsulfonyl )-2-pyrrolidinylthiolacetamido)cephalosporanic Acid.

The title compound was prepared by a procedure in which similar to thatdescribed in Example IV except that [1- I(p-nitrophenylsulfonyl)-2-pyrrolidinylthio]acetic acid R 15 a memberElected from the group conslstlng of was utilized. H, Cl, Br and NO 5 Ris a member selected from the group consisting of l-l and acetoxy; and

El tlAl"fCHNOK.

men a 82 5 2 Z% r 5& '3??? M 15 a member selected from the groupconsisting of Found: c, 40.12; H. 3,67; N, 8.25 H, sodium and potassium.BA SU 6633 .244 B0 BR 4617 250 is (2 1?I 138;? 2235 2. The compound ofclaim 1 which is 7-(2-[1-(p- SA PA 1 1737 bromophenylsulfonyD-Z sT AU6538p 244 pyrrolldmylthio]acetamido)cephalosporamc acid. ST AU SMITH.244 ST AU CHP .976 ST AU 53480 3. The compound of claim 1 which is7-(2-[l-(p- I nitrophenylsulfonyl)-2- what clalmedpyrrolidinylthio]acetamido)cephalosporanic acid.

1. A compound of the formula:

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is7-(2-(1-(p-bromophenylsulfonyl)-2-pyrrolidinylthio)acetamido)cephalosporanicacid.
 3. The compound of claim 1 which is7-(2-(1-(p-nitrophenylsulfonyl)-2-pyrrolidinylthio)acetamido)cephalosporanicacid.